This project concerns the etiological origins of sporadic Alzheimer's disease (AD). While plaques and tangles still define AD, it is thought that oligomeric forms of A? and tau play major roles in the pathogenic mechanism. What triggers the buildup of these toxins, however, and whether the etiological triggers affect toxin impact, remain unknown. The long-term goal of this project therefore is to understand the etiological origins of sporadic AD, with a strategic focus on the pathobiology of AD risk factors. Its central hypothesis is that risk factors have a common ability to stimulate pathogenic A?O buildup, but that each has its own signature regarding the nature and clinical outcome of this buildup. The important relationship between risk factors and A?O pathobiology has not been studied before in unbiased, non-transgenic models. The immediate focus is on two metabolic AD risk factors: hypercholesterolemia (HypC) and type 2 diabetes (T2D). Investigations will address three aims and will provide results that test the central hypothesis and a prediction of potential diagnostic value. AIM 1 ? Determine the pathobiology that makes HypC and T2D act as risk factors for sporadic AD. The working hypothesis is that the dysfunctional metabolic states of HypC and T2D are AD risk factors because they promote the buildup of pathogenic A?Os. AIM 2 ? Establish a mechanistic principle to explain why AD manifests as heterogeneous phenotypes. The working hypothesis is that although the risk factors HypC and T2D each promote buildup of pathogenic A?Os, there is an etiology-sensitive signature to that buildup that influences the cognitive outcome. AIM 3 ? Establish in vivo biomarkers that can diagnose the etiology-sensitive status of A?O neuropathology. The working hypothesis is that tandem imaging of brain A?Os and brain function will optimally diagnose AD in a manner that is etiology-sensitive. Rabbit will be used as a non-transgenic model. Pilot data show that substantial memory dysfunction is caused by diets associated with HypC and T2D. This dysfunction is linked to A?O buildup, and it manifests with an etiology-specific signature. New analytics will establish the impact of HypC and T2D on brain region-selective memory performance, functional and molecular MRI, AD-linked neuropathology, and buildup of distinct A?O species. The approach is the first rigorous investigation into the onset of A?O pathobiology in an animal model unbiased by transgene expression. The expected outcome is establishment of a molecular mechanism to connect risk factors HypC and T2D to sporadic AD. Results are expected, moreover, to establish a platform for future mechanistic studies of the now-burgeoning list of AD risk factors, illustrate the significance of etiology to AD diagnosis and precision medicine, and accelerate development of effective AD treatments and prevention strategies.